Epilepsy is a nervous disorder accompanied by chronic or recurring seizures, which are essentially abnormal brain waves resulting from an abnormal depolarization of brain cells. Epilepsy is caused by malfunction of nervous cells of the brain due to a variety of reasons. Everyone is susceptible.
One out of every 200 people is an epilepsy patient who needs continuous treatment. Epilepsy patients in Korea total an estimated 300,000, with 30,000 new cases reported each year. The occurrence of epilepsy varies with gender and age. Epilepsy occurs more frequently in males than in females, and 75% of patients are attacked by the disease before the age of twenty, and the period from birth to four years of age shows the highest 30% of development of the disease. The rate of incidence is lower after the age of twenty but increases again after the age of sixty.
The seizures differ from person to person. Depending on where the seizure occurs, there are two basic types: generalized seizures and partial (or focal) seizures. A generalized seizure occurs on both sides of the brain, while a partial seizure occurs in a restricted area of the brain.
Partial seizures occur when brain waves start to explode abnormally in a portion of the brain cortex or cerebral hemisphere. Partial seizures can be categorized according to the state of consciousness during convulsions: (1) simple partial seizures, which occur while the patient remains conscious, (2) complex partial seizures, which occur while patients are unconscious, and (3) partial seizures evolving to secondarily generalized seizures.
Generalized seizures occur when brain waves start to explode abnormally on both sides of the brain at once and are categorized according to brain wave activity and seizure characteristics. Absence seizures (or small seizures) cause temporary loss of consciousness and exhibit symptoms such as vacant stares or rapid blinking of the eyes. Tonic-clonic seizures (or large seizures) are characterized by a stiffening of the whole body accompanied by a temporary lose of consciousness and may occur as repeated episodes. Myoclonic seizures exhibit symptoms of brief, shock-like jerks of a muscle group or groups. Atonic seizures (or small movement seizures) have symptoms of sudden exhaustion, to the point of falling down or merely a brief dropping of the head.
Complex partial seizures constitute 36% of epileptic seizures, generalized seizures constitute 23%, simple partial seizures constitute 14%, and the remainder (27%) are unidentified or unclassified.
For the treatment of epilepsy, anti-seizure medicines have been used. Most anti-seizure medicines, however, have side effects, which cause problems in blood vessels or organs. Since the mechanisms of seizures have yet to be fully explained, the treatment of epilepsy is still difficult and limited. Thus, for the development of an effective epilepsy treatment agent, it is important to gain a sufficient understanding of the seizure mechanism.
Absence seizures are characterized by a brief loss of consciousness associated with an electroencephalographic recording of 3 Hz bilaterally synchronous spike-and-wave discharges (SWDs) (Niedermeyer, Clinical Electroencephalography, 1996, 27, 1-21; Willams, Brain, 1950, 67, 50-69). Although earlier studies indicated that thalamic neurons were involved in the genesis of SWDs, more recent experiments demonstrate that the neocortex is the minimal substrate for the generation of SWDs (Steriade and Contreras, Journal of Neurophysiology, 1998, 80, 1439-1455; Avoli and Gloor, Epilepsia, 1981, 22, 443-452; Pellegrini et al., Experimental Neurology, 1979, 64, 155-173). Gamma-butyrolactone, (RS)-baclofen, and bicucullinemethobromide (BMB) are known to evoke absence seizures by inducing SWDs, and 4-aminopyridine (4-AP) is known to induce tonic-clonic seizures.
A series of pharmacological studies suggest that GABAB receptors play a critical role in the genesis of SWDs (Crunelli and Leresche, Trends in Neurosciences, 1991, 14, 16-21). It is known that GABAB receptor agonists exacerbate seizures, whereas GABAB receptor antagonists suppress seizures (Hosford et al., Science, 1992, 257, 393-401; Smith and Fisher, Brain Research, 1996, 729, 147-150; Snead, European Journal of Pharmacology, 1992, 213, 343-349). The anti-absence drug clonazepam is thought to act by diminishing GABAB-mediated inhibitory postsynaptic potentials (IPSPs) in thalamocortical relay (TC) neurons (Gibbs et al., Journal of Neurophysiology, 1996, 76, 2568-79; Huguenare and Prince, 1994). The hyperpolarization of membrane potentials induced by the activation of GABAB receptors evokes rebound burst discharges in TC neurons (Crunelli and Leresche, Trends in Neuroscience, 1991, 14, 16-21; McCormick and Bal, Current Opinion in Neurobiology, 1994, 4, 550-56). This characteristic firing pattern of TC neurons is evolved by low-threshold calcium potentials (LTCPs). Therefore, it has been proposed that low-threshold T-type calcium channels are involved in the genesis of absence seizures in the thalamocortical network (Coulter et al., Annals of Neurology, 1989, 25, 582-593; Crunelli and Leresche, Trends in Neuroscience, 1991, 14, 16-21). It has been supported by a belief that drugs effective in the treatment of absence seizures, such as ethosuximide, exert their anti-absence actions through reducing T-type calcium current (IT) in thalamic neurons (Coulter et al., Annals of Neurology, 1989, 25, 582-593; Kostyuk et al., Neuroscience, 1992, 51, 755-758). In addition, T-type calcium channels were moderately increased in the thalamic neurons of genetic absence epilepsy rats from Strasbourg, a model of spontaneous absence epilepsy (Talley et al., Molecular Brain Research, 2000, 75, 159-165; Tsakiridou et al., Journal of Neuroscience, 1995, 15, 3110-7).
Results from recent studies, however, have led to controversy about the role of IT in the genesis of absence seizures. For example, it was shown that ethosuximide failed to suppress IT, but instead affected other channels such as non-inactivating Na+ channels and Ca2+-activated channels in TC neurons (Leresche et al., Journal of Neuroscience, 1998, 18, 4842-4853). Another controversy arose from the observation that, in the intracellular recording of TC neurons in vivo, the majority of neurons underwent rhythmic sequences of IPSPs and steady hyperpolarization instead of LTCPs during SWDs (Pinault et al., Journal of Physiology (London), 1998, 509, 449-456). Therefore, it is not clear whether T-type calcium channels are involved in the generation of SWDs.
Thus, the present inventors have studied whether T-type calcium channels in TC neurons are directly related to the generation of absence seizures inducing SWDs, and it is proved that absence seizures do not occur in the transgenic mice who have lost the function of α1G protein, an ingredient of T-type calcium channels. The present invention has been accomplished by confirming that the inhibition of the α1G protein prevents the development of epilepsy.